VOLUME
32
䡠
NUMBER
9
䡠
MARCH
20
2014
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
2009 that confirmed the same histology (Fig 1B) but a different molecular profile at sequence analysis, namely EGFR wt (Fig 3B) and KRAS wt. The EGFR analysis (exons 18, 19, 20, and 21) was performed by direct sequencing and confirmed by a therascreen EGFR RGQ PCR Kit (Qiagen, Germantown, MD) on both the 2004 and the 2009 samples. In May 2010, pemetrexed therapy was resumed and administered for six cycles when disease progressed at known sites. The presence of ALK translocation in the 2009 biopsy specimen was detected by an ALK break-apart fluorescent in situ hybridization assay, whereas the fluorescent in situ hybridization analysis of the first specimen from 2004 (performed in the Department of Pathology of Antwerp University Hospital, Antwerp, Belgium) was uninformative. Both the 2004 and the 2009 specimens scored positive by immunohistochemistry (3⫹)1 performed by the Pathology Department at our hospital (Figs 4A and 4B). In September 2010, the patient entered a phase II study of PF-02341066 (crizotinib) in EML4/ALK-positive lung cancer and obtained a partial response after 6 weeks of treatment (Fig 2C, CT scan before crizotinib therapy; Fig 2D, CT scan after 6 weeks of crizotinib therapy) that lasted 25 months. In November 2012, a brain CT scan showed multiple asymptomatic brain lesions but disease stability at other known sites. It was decided that whole-brain radiotherapy (24 Gy) would be performed and that crizotinib treatment would be continued.
Long-Term Response to Gefitinib and Crizotinib in Lung Adenocarcinoma Harboring Both Epidermal Growth Factor Receptor Mutation and EML4-ALK Fusion Gene Case Report A67-year-oldwhitewomanwhohadneversmokedandwasasymptomatic (Eastern Cooperative Oncology Group performance group status of 0) was diagnosed in 2004 with thyroid transcription factor 1–positive, ring cell subtype lung adenocarcinoma, stage IV (pleural implants and effusion, cT1N2M1a, TNM version 7.0; Fig 1A, hematoxylin and eosin staining of the 2004 sample). After six courses of first-line chemotherapy with cisplatin plus gemcitabine, disease stability was observed and she began receiving gefitinib treatment. A partial response was obtained after 3 months (Fig 2A, computed tomography [CT] scan before gefitinib therapy; Fig 2B, CT scan after 3 months of gefitinib therapy), and then disease stability was achieved for 2 years (mutational status at that time was unknown). At disease progression, the patient received carboplatin plus pemetrexed chemotherapy for eight cycles, and stable disease was again achieved. After 1 year without therapy, she experienced disease progression (bone, pleural effusion, and mediastinal nodes). Sequence analysis was performed at this time on pleural biopsies that were obtained at the time of the first diagnosis and showed the L858R (2573T⬍G) mutation at exon 21 of the epidermal growth factor receptor gene (EGFR; Fig 3A) with KRAS wild type (wt). For this reason, the patient began receiving treatment with a different reversible EGFR tyrosine kinase inhibitor (TKI), erlotinib, and after 3 months, she began receiving treatment with an irreversible EGFR TKI (afatinib), which was discontinued after 2 months because of disease progression. In June 2009, third-line chemotherapy with taxotere plus gemcitabine was administered for 10 cycles and stable disease was achieved. A new lung biopsy specimen was obtained in December
A
I N
Discussion Lung cancer in never-smokers is a distinct subtype of non–smallcell lung cancer that seems to be driven by a single genetic event. EGFR (45%)2 and KRAS (15%) mutations coupled with EML4-ALK fusion (9%)3 account for roughly 70% of cases and are thought to be mutually exclusive, although a 3% incidence of double mutations in a sample of 516 patients with lung adenocarcinoma was reported.4 To date, clinically effective targeted therapies exist for patients with EGFR mutations5 and for those with ALK rearrangements.6 At least five case reports of concomitant EGFR mutation and EML4-ALK fusion can be
B
Fig 1. e30
© 2014 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 32, No 9 (March 20), 2014: pp e30-e32
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
A
B
C
D
Fig 2.
found in the literature,7-11 and some authors suggest that the ALK translocation plays a role in resistance to EGFR TKIs (although others have exactly the opposite view). Only one of the reported patients had access to both EGFR TKIs and crizotinib and showed an objective response to the ALK inhibitor alone.11 Here we report the case of a 67-year-old woman, a never-smoker, who presented with metastatic lung adenocarcinoma that was refractory to standard chemotherapy. Her disease responded to both EGFR TKIs and crizotinib, with survival from the time of diagnosis of 7 years. She obtained a partial response after 3 months of gefitinib treatment and then experienced disease stability for 2
years (March 2005 to March 2007). Beginning in September 2010, she received crizotinib and experienced a partial response after six cycles that lasted 25 months. The genetic profile of the disease was different in two biopsy specimens, one obtained at diagnosis in 2004 and the other in 2009, despite an identical histologic phenotype. The first biopsy specimen was EGFR mutated and EML4/ALK translocated, whereas the second was EGFR wt and EML4/ALK translocated (Table 1). To our knowledge, this is the second reported patient with both an EGFR mutation and ALK translocation to be treated with both EGFR TKIs and crizotinib, but the first patient to experience a long-term
A
B Wild-type sequence
Wild-type sequence
Amino acid
Amino acid
Sense
Sense
Antisense Antisense
Case #528
Case #807 Fig 3.
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e31
Chiari et al
A
B
Fig 4.
response to both of these treatments.11 Our interpretation is that the tumor harbored both the EGFR mutation and ALK translocation at the first diagnosis in different neoplastic clones, resulting from two distinct oncogenic events and leading to the same histologic phenotype. We hypothesize that both clones were present at the beginning and that those with the ALK translocation were selected by the TKI therapy. This patient case emphasizes the need for selecting targeted therapies on the basis of molecular analyses performed on tumor samples that are representative of the tumor at different time points in the patient’s clinical history.
Rita Chiari, Simona Duranti, Vienna Ludovini, Guido Bellezza, Anjuta Pireddu, Vincenzo Minotti, Chiara Bennati, and Lucio Crino` Santa Maria della Misericordia Hospital, Perugia, Italy
ACKNOWLEDGMENT
Supported in part by research grants from the Associazione Italiana Ricerca sul Cancro and the Associazione Umbra Contro il Cancro. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
Table 1. Findings From Gene Analysis of Biopsy Specimens in 2004 and 2009 Gene
2004
2009
EGFR ALK (FISH) ALK (IHC)
Exon 21 mutation (L858R) Uninformative 3⫹
wt Positive 3⫹
Abbreviations: EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry; wt, wild type.
REFERENCES 1. Conklin CM, Craddock KJ, Have C, et al: Immunohistochemistry is a reliable screening tool for identification of ALK rearrangement in non-smallcell lung carcinoma and is antibody dependent. J Thorac Oncol 8:45-51, 2013 2. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 3. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566, 2007 4. Kris MG, Johnson BE, Kwiatkowski DJ, et al: Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 29:477s, 2011 (suppl; abstr CRA7506) 5. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009 6. Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010 7. Tiseo M, Gelsomino F, Boggiani D, et al: EGFR and EML4-ALK gene mutations in NSCLC: A case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 71:241-243, 2011 8. Kuo YW, Wu SG, Ho CC, et al: Good response to gefitinib in lung adenocarcinoma harboring coexisting EML4-ALK fusion gene and EGFR mutation. J Thorac Oncol 5:2039-2040, 2010 9. Popat S, Vieira de Arau´jo A, Min T, et al: Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol 6:1962-1963, 2011 10. Sasaki T, Koivunen J, Ogino A, et al: A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 71:60516060, 2011 11. Lee JK, Kim TM, Koh Y, et al: Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation. Lung Cancer 77:460-463, 2012
DOI: 10.1200/JCO.2012.47.7141; published online ahead of print at www.jco.org on January 13, 2014 ■ ■ ■
e32
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
32
䡠
NUMBER
9
䡠
MARCH
20
2014
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
2009 that confirmed the same histology (Fig 1B) but a different molecular profile at sequence analysis, namely EGFR wt (Fig 3B) and KRAS wt. The EGFR analysis (exons 18, 19, 20, and 21) was performed by direct sequencing and confirmed by a therascreen EGFR RGQ PCR Kit (Qiagen, Germantown, MD) on both the 2004 and the 2009 samples. In May 2010, pemetrexed therapy was resumed and administered for six cycles when disease progressed at known sites. The presence of ALK translocation in the 2009 biopsy specimen was detected by an ALK break-apart fluorescent in situ hybridization assay, whereas the fluorescent in situ hybridization analysis of the first specimen from 2004 (performed in the Department of Pathology of Antwerp University Hospital, Antwerp, Belgium) was uninformative. Both the 2004 and the 2009 specimens scored positive by immunohistochemistry (3⫹)1 performed by the Pathology Department at our hospital (Figs 4A and 4B). In September 2010, the patient entered a phase II study of PF-02341066 (crizotinib) in EML4/ALK-positive lung cancer and obtained a partial response after 6 weeks of treatment (Fig 2C, CT scan before crizotinib therapy; Fig 2D, CT scan after 6 weeks of crizotinib therapy) that lasted 25 months. In November 2012, a brain CT scan showed multiple asymptomatic brain lesions but disease stability at other known sites. It was decided that whole-brain radiotherapy (24 Gy) would be performed and that crizotinib treatment would be continued.
Long-Term Response to Gefitinib and Crizotinib in Lung Adenocarcinoma Harboring Both Epidermal Growth Factor Receptor Mutation and EML4-ALK Fusion Gene Case Report A67-year-oldwhitewomanwhohadneversmokedandwasasymptomatic (Eastern Cooperative Oncology Group performance group status of 0) was diagnosed in 2004 with thyroid transcription factor 1–positive, ring cell subtype lung adenocarcinoma, stage IV (pleural implants and effusion, cT1N2M1a, TNM version 7.0; Fig 1A, hematoxylin and eosin staining of the 2004 sample). After six courses of first-line chemotherapy with cisplatin plus gemcitabine, disease stability was observed and she began receiving gefitinib treatment. A partial response was obtained after 3 months (Fig 2A, computed tomography [CT] scan before gefitinib therapy; Fig 2B, CT scan after 3 months of gefitinib therapy), and then disease stability was achieved for 2 years (mutational status at that time was unknown). At disease progression, the patient received carboplatin plus pemetrexed chemotherapy for eight cycles, and stable disease was again achieved. After 1 year without therapy, she experienced disease progression (bone, pleural effusion, and mediastinal nodes). Sequence analysis was performed at this time on pleural biopsies that were obtained at the time of the first diagnosis and showed the L858R (2573T⬍G) mutation at exon 21 of the epidermal growth factor receptor gene (EGFR; Fig 3A) with KRAS wild type (wt). For this reason, the patient began receiving treatment with a different reversible EGFR tyrosine kinase inhibitor (TKI), erlotinib, and after 3 months, she began receiving treatment with an irreversible EGFR TKI (afatinib), which was discontinued after 2 months because of disease progression. In June 2009, third-line chemotherapy with taxotere plus gemcitabine was administered for 10 cycles and stable disease was achieved. A new lung biopsy specimen was obtained in December
A
I N
Discussion Lung cancer in never-smokers is a distinct subtype of non–smallcell lung cancer that seems to be driven by a single genetic event. EGFR (45%)2 and KRAS (15%) mutations coupled with EML4-ALK fusion (9%)3 account for roughly 70% of cases and are thought to be mutually exclusive, although a 3% incidence of double mutations in a sample of 516 patients with lung adenocarcinoma was reported.4 To date, clinically effective targeted therapies exist for patients with EGFR mutations5 and for those with ALK rearrangements.6 At least five case reports of concomitant EGFR mutation and EML4-ALK fusion can be
B
Fig 1. e30
© 2014 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 32, No 9 (March 20), 2014: pp e30-e32
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
A
B
C
D
Fig 2.
found in the literature,7-11 and some authors suggest that the ALK translocation plays a role in resistance to EGFR TKIs (although others have exactly the opposite view). Only one of the reported patients had access to both EGFR TKIs and crizotinib and showed an objective response to the ALK inhibitor alone.11 Here we report the case of a 67-year-old woman, a never-smoker, who presented with metastatic lung adenocarcinoma that was refractory to standard chemotherapy. Her disease responded to both EGFR TKIs and crizotinib, with survival from the time of diagnosis of 7 years. She obtained a partial response after 3 months of gefitinib treatment and then experienced disease stability for 2
years (March 2005 to March 2007). Beginning in September 2010, she received crizotinib and experienced a partial response after six cycles that lasted 25 months. The genetic profile of the disease was different in two biopsy specimens, one obtained at diagnosis in 2004 and the other in 2009, despite an identical histologic phenotype. The first biopsy specimen was EGFR mutated and EML4/ALK translocated, whereas the second was EGFR wt and EML4/ALK translocated (Table 1). To our knowledge, this is the second reported patient with both an EGFR mutation and ALK translocation to be treated with both EGFR TKIs and crizotinib, but the first patient to experience a long-term
A
B Wild-type sequence
Wild-type sequence
Amino acid
Amino acid
Sense
Sense
Antisense Antisense
Case #528
Case #807 Fig 3.
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
e31
Chiari et al
A
B
Fig 4.
response to both of these treatments.11 Our interpretation is that the tumor harbored both the EGFR mutation and ALK translocation at the first diagnosis in different neoplastic clones, resulting from two distinct oncogenic events and leading to the same histologic phenotype. We hypothesize that both clones were present at the beginning and that those with the ALK translocation were selected by the TKI therapy. This patient case emphasizes the need for selecting targeted therapies on the basis of molecular analyses performed on tumor samples that are representative of the tumor at different time points in the patient’s clinical history.
Rita Chiari, Simona Duranti, Vienna Ludovini, Guido Bellezza, Anjuta Pireddu, Vincenzo Minotti, Chiara Bennati, and Lucio Crino` Santa Maria della Misericordia Hospital, Perugia, Italy
ACKNOWLEDGMENT
Supported in part by research grants from the Associazione Italiana Ricerca sul Cancro and the Associazione Umbra Contro il Cancro. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
Table 1. Findings From Gene Analysis of Biopsy Specimens in 2004 and 2009 Gene
2004
2009
EGFR ALK (FISH) ALK (IHC)
Exon 21 mutation (L858R) Uninformative 3⫹
wt Positive 3⫹
Abbreviations: EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry; wt, wild type.
REFERENCES 1. Conklin CM, Craddock KJ, Have C, et al: Immunohistochemistry is a reliable screening tool for identification of ALK rearrangement in non-smallcell lung carcinoma and is antibody dependent. J Thorac Oncol 8:45-51, 2013 2. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 3. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-566, 2007 4. Kris MG, Johnson BE, Kwiatkowski DJ, et al: Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 29:477s, 2011 (suppl; abstr CRA7506) 5. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009 6. Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010 7. Tiseo M, Gelsomino F, Boggiani D, et al: EGFR and EML4-ALK gene mutations in NSCLC: A case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 71:241-243, 2011 8. Kuo YW, Wu SG, Ho CC, et al: Good response to gefitinib in lung adenocarcinoma harboring coexisting EML4-ALK fusion gene and EGFR mutation. J Thorac Oncol 5:2039-2040, 2010 9. Popat S, Vieira de Arau´jo A, Min T, et al: Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol 6:1962-1963, 2011 10. Sasaki T, Koivunen J, Ogino A, et al: A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 71:60516060, 2011 11. Lee JK, Kim TM, Koh Y, et al: Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation. Lung Cancer 77:460-463, 2012
DOI: 10.1200/JCO.2012.47.7141; published online ahead of print at www.jco.org on January 13, 2014 ■ ■ ■
e32
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
